Structure based design and anti-breast cancer evaluation of some novel 4-anilinoquinazoline derivatives as potential epidermal growth factor receptor inhibitors

Zahra Haghighijoo, Zahra Rezaei, Mansooreh Jaberipoor, Samaneh Taheri, Meysam Jani, Soghra Khabnadideh

Abstract


Quinazoline is one of the most widespread scaffolds amongst natural and synthetic bioactive compounds. Recently the quinazoline derivatives and in particular the 4-anilinoquinazolines have attracted much attention for their anticancer properties due to their capability to stabilize the kinase activity of epidermal growth factor receptor (EGFR). A series of fifteen previously designed and synthesized 4-anilinoquinazoline analogs (4-18) were evaluated for cytotoxic activity on two breast cancer cell lines (MCF-7 and MDA-MB-468). Ligand efficiency and binding mode studies were also done and evaluated for their potentially EGFR inhibitory effects in comparison with imatinib and erlotinib as reference drugs. Among the tested 4-anilinoquinazolines, compound 11, which contains diethoxy at phenyl ring and morpholino pendants at positions 5 and 7 of the quinazoline ring, demonstrated the most potent biological activity on both cell lines. Our new quinazoline derivatives with different substituents such as cyclic or linear ethers and flour groups may be a promising cytotoxic lead compounds for further anti-breast cancer research.

Keywords


4-Anilinoquinazoline; Cytotoxic activity; Docking; EGFR.

Full Text:

PDF

References


Polyak K. Heterogeneity in breast cancer. J Clin Invest. 2011;121(10):3786-3788.

Tseng LM, Chen YT, Huang CT, Chu PY, Wang WL, Liu CY, et al. Erlotinib derivative, devoid of EGFR kinase inhibiting effect, induced apoptosis of triple-negative breast cancer cells through modulating Elk-1/CIP2A signaling pathway. AACR. 2016;76(14).

Haines E, Schlienger S, Claing A. The small GTPase ADP-ribosylation factor 1 mediates the sensitivity of triple negative breast cancer cells to EGFR tyrosine kinase inhibitors. Cancer Biol Ther. 2015;16(10):1535-1547.

Noolvi MN, Patel HM. Synthesis, method optimization, anticancer activity of 2,3,7-trisubstituted quinazoline derivatives and targeting EGFR-tyrosine kinase by rational approach: 1st Cancer Update. Arabian J Chem. 2013;6(1):35-48.

Li RD, Zhang X, Li QY, Ge ZM, Li RT. Novel EGFR inhibitors prepared by combination of dithiocarbamic acid esters and 4-anilinoquinazolines. Bioorg Med Chem Lett. 2011;21(12):3637-3640.

Waiker DK, Karthikeyan C, Poongavanam V, Kongsted J, Lozach O, Meijer L, et al. Synthesis, biological evaluation and molecular modelling studies of 4-anilinoquinazoline derivatives as protein kinase inhibitors. Bioorg Med Chem. 2014;22(6):1909-1915.

Mowafy S, Farag NA, Abouzid KA. Design, synthesis and in vitro anti-proliferative activity of 4,6-quinazolinediamines as potent EGFR-TK inhibitors. Eur J Med Chem. 2013;61:132-145.

Lü S, Zheng W, Ji L, Luo Q, Hao X, Li X, et al. Synthesis, characterization, screening and docking analysis of 4-anilinoquinazoline derivatives as tyrosine kinase inhibitors. Eur J Med Chem. 2013;61:84-94.

Nasab RR, Hassanzadeh F, Khodarahmi GA, Mirzaei M, Rostami M, Abadi AJ. Synthesis, characterization, cytotoxic screening, and density functional theory studies of new derivatives of quinazolin-4 (3H)-one Schiff bases. Res Pharm Sci. 2017;12(6):444-455.

Jafari E, Khajouei MR, Hassanzadeh F, Hakimelahi GH, Khodarahmi GA. Quinazolinone and quinazoline derivatives: recent structures with potent antimicrobial and cytotoxic activities. Res Pharm Sci. 2016;11(1):1-14.

Zhu Y, Wang Y, Guan B, Rao Q, Wang J, Ma H, et al. C-kit and PDGFRA gene mutations in triple negative breast cancer. Int J Clin Exp Pathol. 2014;7(7):4280-4285.

Wang YL, Overstreet AM, Chen MS, Wang J, Zhao HJ, Ho PC, et al. Combined inhibition of EGFR and c-ABL suppresses the growth of triple-negative breast cancer growth through inhibition of HOTAIR. Oncotarget. 2015;6(13):11150-11161.

Haghighijoo Z, Rezaei Z, Taheri S, Jani M, Khabnadideh S. A rapid and convenient method for synthesis of anilinoquinazoline: an improved synthesis of erlotinib derivatives. Trends Pharmacol Sci. 2015;1(3):173-178.

Haghighijoo Z, Eskandari M, Khabnadideh S. Method optimization for synthesis of trisubstitued quinazoline derivatives. Med Res Arch. 2017;5(5).

Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods. 1983; 65(1-2):55-63.

Mohammadi-Farani A, Foroumadi A, Rezvani Kashani M, Aliabadi A. N-Phenyl-2-p-tolylthiazole-4-carboxamide derivatives: Synthesis and cytotoxicity evaluation as anticancer agents. Iran J Basic Med Sci. 2014;17(7):502-508.

Aliabadi A, Hasanvand Z, Kiani A, Mirabdali SS. Synthesis and in-vitro cytotoxicity assessment of N-(5-(Benzylthio)-1, 3, 4-thiadiazol-2-yl)-2-(4-(trifluoromethyl) phenyl) acetamide with potential anticancer activity. Iran J Pharm Res. 2013;12(4): 687-693.

Abad-Zapatero C, Metz JT. Ligand efficiency indices as guideposts for drug discovery. Drug Discov Today. 2005;10(7):464-469.

Abad-Zapatero C, Perišić O, Wass J, Bento AP, Overington J, Al-Lazikani B, et al. Ligand efficiency indices for an effective mapping of chemico-biological space: the concept of an atlas-like representation. Drug Discov Today. 2010;15 (19-20):804-811.

Abad-Zapatero C. Ligand efficiency indices for effective drug discovery. Expert Opin Drug Discov. 2007;2(4):469-488.

Stamos J, Sliwkowski MX, Eigenbrot C. Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4-anilinoquinazoline inhibitor. J Biol Chem. 2002;277(48):46265-46272.

Gazdar AF. Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors. Oncogene. 2009;28(Suppl 1):S24-S31.

Park JH, Liu Y, Lemmon MA, Radhakrishnan R. Erlotinib binds both inactive and active conformations of the EGFR tyrosine kinase domain. Biochem J. 2012;448(3):417-423.


Refbacks

  • There are currently no refbacks.


Creative Commons Attribution-NonCommercial 3.0

This work is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License which allows users to read, copy, distribute and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited properly.